Combination-based antibiotic treatments are gaining increasing attention. Here, Lázár et al. systematically quantify Staphylococcus aureus survival under a range of antibiotic combinations, revealing that reciprocal suppression — where the combination is weaker than each drug alone — emerges in long-term population clearance. Drug efficacy is further reduced as more drugs are added; however, adding persistence-targeting drugs overcomes these suppressive drug mixes. Reciprocal suppressive drug pairs can select against strains resistant to either of the single drugs.